Idiopathic dilated cardiomyopathy (DCM) is a heritable, genetically heterogeneous disorder that causes progressive human heart failure and death. Candidate gene and family-based mapping studies have uncovered defects in diverse molecular pathways, yet DCM remains an idiopathic condition in the vast majority of patients. This proposal is based on recruitment and phenotypic characterization of a large cohort of unrelated subjects with DCM, including multigenerational families and multiple children with early-onset heart failure. The first aim is to identify novel genes for autosomal dominant DCM by combined genetic linkage and exome sequencing strategies. The second aim is to identify inherited and de novo mutations that underlie pediatric DCM. The third aim is to determine the frequency and spectrum of mutations in novel DCM genes in a well-characterized cohort. These aims are designed to overcome existing technological barriers to DCM gene discovery by capitalizing on the emerging technology of whole-exome sequencing. The overall objectives of this work are to provide new insight into the molecular basis of myopathic heart failure, advance knowledge of the genetic basis of pediatric-onset DCM, and improve prediction, prevention, and treatment of DCM.